Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991.
Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991.
复制标题
DOI：
--
复制
发表时间：
2002-07
影响因子：
5.7
通讯作者：
H. Seimiya;T. Oh‐hara;Tsuneji Suzuki;I. Naasani;T. Shimazaki;K. Tsuchiya;T. Tsuruo
中科院分区：
文献类型：
--
作者：
H. Seimiya;T. Oh‐hara;Tsuneji Suzuki;I. Naasani;T. Shimazaki;K. Tsuchiya;T. Tsuruo
流行病学研究表明茶儿茶素具有有效的抗癌作用。此前，我们曾报道（I. Naasani 等人，Biochem. Biophys. Res. Commun.，249：391-396，1998）表没食子儿茶素没食子酸酯（EGCG）是一种主要的茶儿茶素，可强烈直接抑制端粒酶，端粒酶是一种维持端粒的核糖核蛋白，与肿瘤发生有关。在这里，我们描述了新合成的化合物 MST-312、MST-295 和 MST-199，它们是比 EGCG 更有效的端粒酶抑制剂。用无毒剂量的每种药物连续治疗人单母细胞白血病 U937 细胞，导致端粒进行性缩短，最终生长速度降低，同时诱导衰老相关的 β-半乳糖苷酶活性。特别是，就MST-312而言，端粒缩短所需的有效剂量为1-2μM，比EGCG低15至20倍。这些化合物可能为治疗癌症提供新的化疗策略。
Epidemiological studies suggest potent anticancer effects of tea catechins. Previously, we have reported (I. Naasani et aL, Biochem. Biophys. Res. Commun., 249: 391-396, 1998) that epigallocatechin gallate (EGCG), a major tea catechin, strongly and directly inhibits telomerase, a ribonucleoprotein that maintains telomeres and has been implicated in tumorigenesis. Here, we describe newly synthesized compounds MST-312, MST-295, and MST-199, as more effective telomerase inhibitors than EGCG. Continuous treatment of human monoblastoid leukemia U937 cells with a nontoxic dose of each drug caused progressive telomere shortening and eventual reduction of growth rate accompanied by induction of the senescence-associated beta-galactosidase activity. Particularly, in the case of MST-312, the effective dose required for the telomere shortening was 1-2 microM, which was 15- to 20-fold lower than that of EGCG. These compounds may provide a novel chemotherapeutic strategy for the treatment of cancers.